(1) Field of the Invention
The present invention relates to a process for the preparation of 9-beta-anomeric nucleoside analogs. In particular the present invention relates to the preparation of 2′-deoxy, 3′-deoxy, 2′-deoxy-2′-β-fluoro and 2′,3′-dideoxy-2′-fluoro purine nucleoside analogs. The process avoids the formation of 7-position isomers because of a protective group in the 6-position.
(2) Description of Related Art
Prior glycosylation procedures in which the 2-deoxy-β-D- or L-ribofuranosyl (2-deoxy-β-D- or L-erythro-pentofuranosyl), 3-deoxy-β-D- or L-ribofuranosyl (3-deoxy-β-D- or L-erythro-pentofuranosyl), 2-deoxy-2-fluoro-β-D- or L-arabinofuranosyl (2-deoxy-2-fluoro-β-D- or L-threo-pentofuranosyl), 2,3-dideoxy-2-fluoro-β-D- or L-arabinofuranosyl (2,3-dideoxy-2-fluoro-β-D- or L-threo-pentofuranosyl) or the β-D- or L-arabinofuranosyl moiety is introduced into an aglycon moiety invariably provide anomeric mixtures as well as positional isomers which results in very low yield of the desired nucleoside. In view of these difficulties, a four step deoxygenation procedure using phenoxythiocarbonylation was developed to obtain the 2′-deoxy nucleosides (J.A.C.S. 1983, 105, 4059) or the 2,3-dideoxy-2-fluoro-β-D-arabinofuranosyl nucleosides (J. Med. Chem. 1990, 33, 978). The 3′-deoxyadenosine (Cordycepin) was also made starting from adenosine via an 2′,3′-anhydroadenosine route followed by the epoxide ring opening (Synthesis. 1985, 1108).
What all these procedures lack, however, is an improved process that does not require the availability of the preformed nucleoside and also is applicable in the presence of halo heterocyclic (preferably 2-halo) derivatives, which are the most useful for further nucleophilic displacements. Later on, Robins et al. (J.A.C.S. 1984, 106, 6379) developed a stereospecific sodium salt glycosylation procedure for the synthesis of 2′-deoxy nucleosides. This procedure eliminates the formation problem of the α-anomeric nucleoside but the positional isomer question (N-9 and N-7) remained to be solved. Moreover the tedious silica gel column purification between the two very similar positional isomers is unacceptable for large scale preparation of 2′-deoxy nucleosides. The sodium salt glycosylation procedure was also explored for the synthesis of 2′-F-ara-ddA (J. Med. Chem. 1994, 37, 821) and again the separation of the isomers and a suitable large scale method remained to be solved. Marquez et al. had also reported (J. Med. Chem. 1990, 33, 978 and 1991, 34, 1647) the coupling of purine or 6-chloropurine with the 2′-β-fluoro-bromo sugar to obtain an expected mixture of four isomeric nucleosides and the time consuming purification of the reaction mixture through silica gel column chromatography. Moreover for the synthesis of adenosine type nucleosides (having the 6-amino group in purine moiety), the treatment of the 6-chloro blocked nucleoside with methanolic ammonia at elevated temperature and pressure to obtain the 6-amino purine nucleoside is the method of choice. This conversion often requires to carry out the reaction in steel bomb or sealed tube at elevated temperature. Therefore a more expedient and flexible approach that provided a more simplified process to the target biologically active nucleosides is needed.
Related art: U.S. Pat. No. 4,760,137 to Robins et al; Ikehara, M, et al., J. Amer. Chem. Soc. 87:3 (1965); Communications to the Editor, Vol. 85, pg. 2344 (1963); U.S. Pat. No. 5,459,255 to Cook et al.; Furukawa, Y., et al., Chem. Pharm. Bull. 16(6)1076-1080 (1968).